Antihypertensive benzopyran derivatives

ABSTRACT

Disclosed herein are novel benzopyrans represented by formula (I) ##STR1## wherein R 1  is trifluoromethoxy or β, β, β-trifluoroethoxy; R 2  and R 3  are independently selected from the group consisting of hydrogen, lower alkyl containing 1 to 5 carbon atoms, cyclo lower alkyl containing 5 to 8 carbon atoms, ##STR2## or R 2  and R 3  are joined to form (--CH 2  --) n  wherein n is 4 to 7; or R 2  and R 3  are joined together to form (--CH 2  --) m  CO-- wherein m is 3 to 6; or R 2  and R 3  are joined together to form ##STR3## wherein R 4  is selected from the group consisting of hydrogen, alkoxy containing 1 to 5 carbon atoms, amino or mono- or disubstituted alkyl amino wherein said alkyl groups contain 1 to 5 carbon atoms and the pharmaceutically acceptable salts and solvates thereof, to a process for preparing them, to pharmaceutical compositions containing them, and to their use in the treatment of hypertension, asthma, irritable bladder syndrome, and irritable bowel syndrome.

This is a continuation-in-part application of copending application U.S.Ser. No. 07/753,256, filed Aug. 30, 1991, abandoned which, in turn, is acontinuation application of copending application U.S. Ser. No.07/502,084, filed Mar. 29, 1990, now abandoned.

BACKGROUND OF THE INVENTION

The present invention relates to novel benzopyrans havingpharmacological activity, to a process for preparing them, topharmaceutical compositions containing them, and to their use in thetreatment of hypertension.

European Patent Publication No. 158,923 discloses classes of chromansthat are described as having blood pressure lowering activity.

The present invention discloses compounds represented by formula (I)##STR4## wherein R¹ is trifluoromethoxy or β, β, β-trifluoroethoxy; R²and R³ are independently selected from the group consisting of hydrogen,lower alkyl containing 1 to 5 carbon atoms, cyclo lower alkyl containing5 to 8 carbon atoms, ##STR5## or R² and R³ are joined to form (--CH₂--)_(n) wherein n is 4 to 7; or R² and R³ are joined together to form(--CH₂ --)_(m) CO-- wherein m is 3 to 6; or R² and R³ are joinedtogether to form ##STR6## wherein R⁴ is selected from the groupconsisting of hydrogen, alkoxy containing 1 to 5 carbon atoms, amino ormono- or disubstituted alkyl amino wherein said alkyl groups contain 1to 5 carbon atoms and the pharmaceutically acceptable salts and solvatesthereof.

Preferred aspects of the present invention are compounds of formula (I)wherein R¹ is trifluoromethoxy and R² and R³ are joined to form ##STR7##and the pharmaceutically acceptable salts and solvates thereof.

The preferred compounds of the present invention are designated

2-[2,2-dimethyl-6-(trifluoromethoxy)-2H-1-benzopyran-4-yl]-2,3-dihydro-1H-isoindol-1-one,

2-[2,2-dimethyl-6-(trifluoromethoxy)-2H-1-benzopyran-4-yl]-1,2-dihydro-3H-pyrrolo[3,4-c]pyridin-3-one,

and the pharmaceutically acceptable salts thereof.

The present invention provides a process for the production of compoundsof formula (I) which comprises the reaction of a compound of formula(II) ##STR8## wherein R¹, R², and R³ are as defined above with NaH, CS₂and MeI to form the substituted intermediate xanthate compound offormula (III) ##STR9## wherein R¹, R², and R³ are as defined above andheating said xanthate compound of formula (III) to produce the compoundof formula (I).

Alternatively, compounds of formula (II) wherein R¹, R², and R³ are asdefined above are condensed with methanesulfonyl chloride in thepresence of triethylamine to afford the intermediate methanesulfonate ofthe formula (IIIa) ##STR10## wherein R¹, R², and R³ are as definedabove. Said methanesulfonate (IIIa) is treated sequentially with sodiumiodide (at room temperature) and 1,8-diazabicyclo[5.4.0]undec-7-ene(DBU) at slightly elevated temperature to produce the compound offormula (I).

Some of the required compounds of formula (II) can be prepared by thereaction of a compound of formula (IV) ##STR11## where R₁ ¹ is R¹ asdefined hereinbefore or a group or atom convertible thereto, with acompound of formula (V) ##STR12## wherein X is chlorine, bromine, oriodine; R⁴ is as defined above; and p is 1 or 2 to produce the compoundof formula (VIIa). ##STR13## wherein R¹, R⁴ and p are as defined above.

Some of the required compounds of formula (II) can be prepared by thereaction of a compound of formula (IV) ##STR14## wherein R₁ ¹ is R¹ asdefined hereinbefore or a group or atom convertible thereto, with acompound of formula (VIa) or (VIb) ##STR15## wherein R⁴ is as definedabove to produce the compound of formula (VIIa), wherein p is 1 or VIIb##STR16## wherein R¹ is as defined above.

The present invention provides a process for the reaction of thecompound (VIIa) with NaH, CS₂ and MeI to form the substitutedintermediate xanthate compound of formula (VIII) ##STR17## wherein R¹and R⁴ are as defined above.

The intermediate xanthate (VIII), without isolation, is heated anddirectly converted to the desired product of formula (IX) ##STR18##wherein R¹ and R⁴ are as defined above.

It is particularly preferred that the reaction between the compounds offormula (IV) and (V) is carried out under alkylation conditions so as tofacilitate the formation of the desired bonds, for example, by heatingin the presence of potassium carbonate.

The present invention also provides a process for the reaction of thecompound (VIIb) with methanesulfonyl chloride in the presence oftriethylamine to form the methanesulfonate of formula (X) ##STR19##wherein R¹ is as defined above.

The intermediate methanesulfonate (X) is sequentially treated withsodium iodide at room temperature followed by1,8-diazabicyclo[5.4.0]undec-7-ene at 70° to 90° C. to produce thedesired product of formula (XI) ##STR20## wherein R¹ and R⁴ are asdefined above.

Examples of conversions of a group or atom from R¹ ₁ into R¹ aregenerally known in the art of synthetic chemistry. For example, if it isdesired to obtain a compound of formula (I) wherein R¹ is atrifluoroethoxy group it is possible to convert a compound of formula(I) wherein R¹ is a hydroxy group or a protected hydroxy group to thedesired trifluoroethoxy group by deprotecting the hydroxy group andalkylating the hydroxy group in a conventional manner. Examples ofprotecting agents and their addition and removal are generally known inthe art.

The compounds of this invention are capable of forming acid additionsalts with therapeutically acceptable acids. The acid addition salts areprepared by reacting the base form of the appropriate compound offormula (I) with one or more equivalents, preferably with an excess, ofthe appropriate acid in an organic solvent, for example, diethyl etheror an ethanol diethyl ether mixture.

These salts, when administered to a mammal, possess the same or improvedpharmacologic activities as the corresponding bases. For many purposesit is preferable to administer the salts rather than the basiccompounds. Suitable acids to form these salts include the common mineralacids, e.g. hydrohalic, sulfuric or phosphoric acid; the organic acids,e.g. ascorbic, citric, lactic, aspartic or tartaric acid; and acidswhich are sparingly soluble in body fluids and which impart slow-releaseproperties to their respective salts, e.g. pamoic or tannic acid orcarboxymethyl cellulose. The preferred salt is the hydrochloride salt.The addition salts thus obtained are the functional equivalent of theparent base compound in respect to their therapeutic use. Hence, theseaddition salts are included within the scope of this invention and arelimited only by the requirement that the acids employed in forming thesalts be therapeutically acceptable.

The compounds of formulas (IV) and (V) are known compounds or can beprepared by conventional procedures from known compounds.

As mentioned previously, the compounds of formula (I) have been found tohave blood-pressure lowering activity. They are therefore useful in thetreatment of hypertension. These compounds may also be useful in thetreatment of asthma, irritable bladder syndrome, and irritable bowelsyndrome.

The present invention accordingly provides a pharmaceutical compositionwhich comprises a compound of this invention and a pharmaceuticallyacceptable carrier. In particular, the present invention provides anantihypertensive pharmaceutical composition which comprises anantihypertensive effective amount of a compound of this invention and apharmaceutically acceptable carrier.

The compositions are preferably adapted for oral administration.However, they may be adapted for other modes of administration, forexample, parenteral administration for patients suffering from heartfailure.

In order to obtain consistency of administration, it is preferred that acomposition of the invention is in the form of a unit dose. Suitableunit dose forms include tablets, capsules and powders in sachets orvials. Such unit dose forms may contain from 0.1 to 100 mg of a compoundof the invention and preferably from 2 to 50 mg. Still further preferredunit dosage forms contain 5 to 25 mg of a compound of the presentinvention. The compounds of the present invention can be administeredorally at a dose range of about 0.01 to 100 mg/kg or preferably at adose range of 0.1 to 10 mg/kg. Such compositions may be administeredfrom 1 to 6 times a day, more usually from 1 to 4 times a day.

The compositions of the invention may be formulated with conventionalexcipients, such as a filler, a disintegrating agent, a binder, alubricant, a flavoring agent and the like. They are formulated inconventional manner, for example in a manner similar to that used forknown antihypertensive agents, diuretics and β-blocking agents.

The present invention further provides a compound of the invention foruse as an active therapeutic substance. Compounds of formula (I) are ofparticular use in the treatment of hypertension.

The present invention further provides a method of treating hypertensionin mammals including man, which comprises administering to the afflictedmammal an antihypertensive effective amount of a compound or apharmaceutical composition of the invention.

Synthetic Process A relates to the preparation of a compound of formula(I) ##STR21## wherein when R² is hydrogen R³ is benzoyl, furoyl or R²and R³ are joined to form isoquinolone or isoindolone ##STR22## whereinR¹ is defined above; X is chlorine, bromine or iodine; R⁶ is benzoyl,furoyl, or ##STR23## wherein p is 1 or 2; R⁷ is lower alkyl containing 1to 5 carbon atoms, cyclo lower alkyl containing 5 to 8 carbon atoms, orbenzyl; R⁸ is benzoyl or furoyl; and R⁴ is as defined above.

The production of preferred compounds of the present invention isillustrated by Synthetic Process B and Synthetic Process C ##STR24##

The following examples further illustrate this invention:

EXAMPLE 1 Preparation of p-Trifluoromethoxy Phenol

p-Trifluoromethoxy aniline (49.60 g) was added rapidly dropwise tovigorously stirred 9N aqueous H₂ SO₄ (500 mL) at 40° C. The mixture washeated to dissolve the solid, then cooled to 0° C. To the fine whitesuspension, a solution of sodium nitrite (19.46 g in 50 mL of H₂ O) wasadded portionwise until an immediate positive KI/starch test result wasobtained. This cold solution of diazonium salt was added rapidlydropwise to 9N aqueous H₂ SO₄ (500 mL) at 110° C. Stirring and heatingwas continued for 2.5 hours. The mixture was cooled to 10° C. andextracted with diethyl ether (3×500 mL). The combined organic layerswere dried (MgSO₄), filtered and evaporated in vacuo, then flashchromatographed on SiO₂ using diethyl ether as eluant to give 35.0 g ofthe desired phenol as a light brown oil. The oil was distilled(b.p.=75°-80° C. at 20 torr.) to afford a yellow liquid.

NMR (CDCl₃): δ5.06 (1H, s), 6.83 (2H, d, J=9.2 Hz), 7.11 (2H, d, J=9.2Hz)

EXAMPLE 2 Preparation of1-[(1,1-Dimethyl-2-propynyl)oxy]-4-(trifluoromethoxy)benzene

To a solution of p-trifluoromethoxy phenol (30.69 g), and2-methyl-2-chloro-3-butyne (53.00 g) in dry acetonitrile (350 mL) wasadded potassium iodide (14.30 g) followed by potassium carbonate (95.25g). This reaction mixture was heated at 70°-80° C. for four days thencooled to room temperature and filtered through celite. The precipitatewas washed with dichloromethane and the washings were added to theacetonitrile. The organics were evaporated in vacuo and the oil wastaken up in 250 mL of dichloromethane. The organics were washed withwater (2×100 mL) and dilute aqueous sodium thiosulfate (2×100 mL), dried(MgSO₄), filtered and evaporated in vacuo to leave a dark brown-orangeoil. Flash column chromatography on SiO₂ using hexane/Et₂ O (5/1)afforded 34.73 g of the pure product.

NMR (CDCl₃) δ1.64 (6H, s), 2.60 (1H, s), 7.05-7.30 (4H, m)

EXAMPLE 3 Preparation of2,2-Dimethyl-6-(trifluoromethoxy)-2H-1-benzopyran

A solution of1-[(1,1-dimethyl-2-propynyl)oxy]-4-(trifluoromethoxy)benzene (16.25 g)in 60 mL of quinoline was heated to 175° C. for 2 hours. The solutionwas cooled to room temperature then ether (250 mL) was added. Thismixture was stirred for 15 minutes then decanted from any precipitatedtars. The ether solution was washed with 1N aqueous hydrochloric acid(3×200 mL) then water (1×200 mL) and dried (K₂ CO₃). The filtered ethersolution was evaporated and flash chromatographed on SiO₂ usinghexane/ethyl acetate (5/1) as eluant to afford 13.92 g (85%) of thedesired bicyclic compound.

Alternate Preparation of2,2-Dimethyl-6-(trifluoromethoxy)-2H-1-benzopyran

A solution of the1-[(1,1-dimethyl-2-propynyl)oxy]-4-(trifluoromethoxy)benzene (29.05 g)in 100 mL of chlorobenzene (b.p.=132° C.) was heated to reflux for 24hours. The reaction mixture was cooled and the solvent removed in vacuo.The oily residue was flash chromatographed on SiO₂ using hexane/ethylacetate (5/1) as eluant to afford 19.72 g of the desired bicycliccompound.

NMR (CDCl₃) δ1.42 (6H, s), 5.67 (1H, d, J=10 Hz), 6.28 (1H, d, J=10 Hz),6.78 (1H, d, J=5.5 Hz), 6.83 (1H, d, J=2 Hz), 6.94 (1H, dd, J=5.5 Hz, 2Hz)

EXAMPLE 4 Preparation of1a,7b-Dihydro-2,2-dimethyl-6-(trifluoromethoxy)-2H-oxireno[c][1]benzopyran

To a solution of 2,2-dimethyl-6-(trifluoromethoxy)-2H-1-benzopyran(14.37 g) in dichloromethane (40 mL) at 0° C. was added a solution ofm-chloroperoxybenzoic acid (mCPBA) (14.22 g) in dichloromethane (160 mL)dropwise. After the addition was complete the ice bath was removed andthe temperature allowed to warm slowly to 15° C. whilst stirring for 18hours. The reaction mixture was filtered, and the precipitate was washedwith dichloromethane (50 mL). The combined filtrate was washed with 25%aqueous sodium thiosulfate (2×100 mL), and 50% aqueous sodiumbicarbonate (2×100 mL), dried (MgSO₄), filtered and evaporated in vacuo.The orange oil was flash chromatographed on SiO₂ using hexane/ether(4/1) as eluant to afford 13.36 g of the epoxide as a light yellow oil,which solidified upon standing.

NMR (CDCl₃) δ1.25 (3H, s), 1.58 (3H, s), 3.49 (1H, d, J=4 Hz), 3.86 (1H,d, J=4 Hz), 6.78 (1H, d, J=8.5 Hz), 7.11 (1H, dd, J=8.5 Hz and 2 Hz),7.22 (1H, d, J=2 Hz)

EXAMPLE 5 Preparation oftrans-2,3-Dihydro-2,2-dimethyl-3-hydroxy-6-(trifluoromethoxy)-2H-1-benzopyran-4-amine

To a solution of1a,7b-dihydro-2,2-dimethyl-6-(trifluoromethoxy)-2H-oxireno[c][1]-benzopyran(6.18 g) in absolute ethanol (30 mL) at 0° C. was added ammoniumhydroxide (45 mL). The reaction mixture was capped with a rubber septumand stirred for four days. The reaction mixture was evaporated in vacuoto remove ethanol and water and the oil was taken up in dichloromethane,dried (Na₂ SO₄) filtered and concentrated in vacuo. The residue wasflash chromatographed on SiO₂ using dichloromethane/methanol (5/1) aseluant to afford the amino-alcohol, m.p. 176°-182° C. (dec.)recrystallized from chloroform.

Two of the above reactions were run simultaneously to obtain 8.95 g ofproduct.

NMR (DMSO-d₆) δ1.07 (3H, s), 1.35 (3H, s), 3.20 (1H, d, J=9.2 Hz), 3.52(1H, d, J=9.2 Hz), 6.76 (1H, d, J=9 Hz), 7.08 (1H, dd, J=9 Hz, 1.5 Hz),7.51 (1H, d, J=1.5 Hz)

EXAMPLE 6 Preparation oftrans-2-[2,3-Dihydro-2,2-dimethyl-3-hydroxy-6-(trifluoromethoxy)-4H-1-benzopyran-4-yl]-2,3-dihydro-1H-isoindol-1-one

To a solution oftrans-2,3-dihydro-2,2-dimethyl-3-hydroxy-6-(trifluoromethoxy)-2H-1-benzopyran-4-amine(13.86 g) and methyl 2-formylbenzoate (9.03 g) in 200 mL of dry methanolwas added 120 mL of a 0.5 molar solution of zinc chloridesodiumcyanoborohydride (0.06 moles each) in dry methanol. After one hour themixture was warmed to 50°-55° C. and held there with stirring for 14hours.

The cooled reaction mixture was quenched with 120 mL of saturatedaqueous sodium bicarbonate and the methanol was removed in vacuo. 120 mLof water was added to the residue which was then extracted withdichloromethane (3×200 mL). The combined extracts were washed with water(2×300 mL), dried over K₂ CO₃, filtered then evaporated to leave anoff-white solid.

This solid was dissolved in 500 mL of hot toluene; the mixture was thenheated to reflux for 4 to 5 hours. The solution was then cooled and awhite precipitate began to form. The mixture was cooled to 0° C. for 0.5hours during which time a thick mass of white crystals formed. Thesecrystals were collected by vacuum filtration, washed with hexane/toluene(4/1) and dried in vacuo to yield 18.30 g (93%) of analytically pureproduct as a white flocculent solid, m.p. 212°-213° C.

Alternate Preparation oftrans-2-[2,3-Dihydro-2,2-dimethyl-3-hydroxy-6-(trifluoromethoxy)-4H-1-benzopyran-4-yl]-2,3-dihydro-1H-isoindole-1-one

To a solution oftrans-2,3-dihydro-2,2-dimethyl-3-hydroxy-6-(trifluoromethoxy)-2H-1-benzopyran-4-amine(3.85 g) and methyl 2-bromomethylbenzoate (3.11 g) in dry acetonitrile(80 mL) was added potassium iodide (1.13 g) then potassium carbonate(powdered, 5.63 g). The reaction mixture was stirred under nitrogen atroom temperature for 1 hour then heated in a 75°-80° C. oil bath for 24hours. The cooled mixture was vacuum filtered through celite. Theprecipitate was washed with ethyl acetate (75 mL), and the filtrateswere combined and evaporated. The residue was taken up in ethyl acetate(175 mL), washed with water (2×100 mL) then 25% aqueous sodiumthiosulfate (2×100 mL), dried (MgSO₄), filtered and evaporated in vacuo.The resultant oil was crystallized from dichloromethane/ethyl acetate(5/1). The crystals were collected, washed with ether, and dried invacuo to afford the desired compound in 48% yield, m.p. 212°-213° C.

NMR (DMSO-d₆) δ1.24 (3H, s), 1.46 (3H, s), 3.91 (1H, br), 4.06 (1H, brd), 4.48 (1H, br d), 5.24 (1H, br s), 5.77 (1H, d, J=5.8 Hz), 6.70 (1H,br s), 6.92 (1H, d, J=8.9 Hz), 7.17 (1H, dd, J=8.9 Hz and 2.6 Hz),7.50-7.66 (3H, m), 7.78 (1H, d, J=7.5 Hz)

Anal. Calcd.: C, 61.07; H, 4.61; N, 3.56; Found: C, 60.92; H, 4.87; N,3.35.

EXAMPLE 72-[2,2-Dimethyl-6-(trifluoromethoxy)-2H-1-benzopyran-4-yl]-2,3-dihydro-1H-isoindol-1-one

To a stirred solution oftrans-2-[2,3-dihydro-2,2-dimethyl-3-hydroxy-6-(trifluoro-methoxy)-4H-1-benzopyran-4-yl]-2,3-dihydro-1H-isoindol-1-one(560 mg) in dry THF at room temperature was added sodium hydride (107mg, 80% in oil). After 10 minutes, a catalytic amount of imidazole wasadded and the mixture was warmed to 40° C. for 30 minutes. The oil bathwas lowered and carbon disulfide (0.30 mL) was added. After 10 minutesthe mixture was warmed to 40° C. for 30 minutes. The oil bath waslowered and methyl iodide (0.31 mL) was added. After 10 minutes themixture was warmed to 40° C. for 45 minutes. The reaction mixture wasthen cooled and evaporated to a yellow solid. Methylenechloride (25 mL)was added and the solid removed by filtration. The filtrate wasevaporated to a yellow oil.

This oil was heated neat to 165°-170° C. for 2 hours. TLC of an aliquot(eluantether/hexane, 4/1) showed no xanthate and one less polarmaterial. The reaction mixture was flash chromatographed on silica gelusing ether/hexane (3/1) as eluant to afford, after evaporation, a whitefoam. The foam was crystallized using warm hexane and collected byvacuum filtration. Yield of product after vacuum drying was 315 mg (59%yield).

NMR (CDCl₃, 400 MHz) δ1.54 (6H, s), 4.62 (2H, s), 5.83 (1H, s), 6.76(1H, d, J=2.6 Hz), 6.85 (1H, d, J=8.8 Hz), 7.01 (1H, dd, J=8.8 Hz and2.6 Hz), 7.49 (1H, d), 7.53 (1H, t), 7.62 (1H, dt) and 7.93 (1H, d)

IR (KBr): 1695, 1250, 1160 and 735 cm⁻¹

MS: m/e 375 (M+)

Anal. Calcd.: C, 64.00; H, 4.30; N, 3.73; Found: C, 63.84; H, 4.23; N,3.83.

EXAMPLE 82-[2,2-Dimethyl-6-(trifluoromethoxy)-2H-1-benzopyran-4-yl]-1,2-dihydro-3H-pyrrolo[3,4-c]pyridin-3-one

To a stirred solution of2-[(3S,4R)-3,4-dihydro-3-hydroxy-2,2-dimethyl-6-(trifluoro-methoxy)-2H-1-benzopyran-4-yl]-1,2-dihydro-3H-pyrrolo[3,4-c]pyridin-3-one(60 mg) in dry tetrahydrofuran (1 mL) was added triethylamine (0.027mL). The mixture, under a nitrogen atmosphere, was chilled to 0° C.,methanesulfonyl chloride (0.015 mL) was added, and stirring wascontinued for 16 hours. The reaction mixture which was allowed to warmto room temperature was treated with ethyl acetate (12 mL) and washedwith water (2×8 mL). The organic extract was dried (MgSO₄), evaporated,and flash chromatographed on SiO₂ using ether/ethyl acetate (3/2) toafford pure methane sulfonate (55 mg).

To a solution of the methanesulfonate dissolved in dry dimethylformamide(1.5 mL) was added sodium iodide (57 mg) and the resulting mixture wasstirred for 12 hours at room temperature and 3 hours at 45°-50° C. Thereaction vessel was removed from the heating bath,1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) (0.045 mL) was added, andheating was resumed for 3 hours at 80°-85° C. The reaction mixture wascooled and treated with ethyl acetate and washed with water (4×10 mL).The organic phase was dried (K₂ CO₃) and evaporated to a brown oil. Thecrude product was purified by flash chromatography on silica gel[ether/ethyl acetate (1/1)] to afford the above titled product (25.5 mg)as a clear oil.

NMR (CDCl₃) δ1.56 (6H, s), 4.76 (2H, s), 5.89 (1H, s), 6.72 (1H, d, J=2Hz), 6.90 (1H, d, J=8 Hz), 7.06 (1H, dd, J=8 Hz, 2 Hz), 7.68 (1H, d, J=5Hz), 8.90 (1H, d, J=5 Hz), 9.22 (1H, s).

Pharmacological Data

Male Okamoto-Aoki spontaneously hypertensive rats (SHR) ranging inweight from 250-400 g were anesthetized with halothane. Their leftfemoral arteries and veins were cannulated with polyethylene tubing ofthe appropriate size (i.d. 0.023", o.d. 0.038"). Each animal was placedin a Bollman cage, and the tail, along with two cannulas, was extendedthrough a hole in one end of the cage. The tail was taped securely to afirm rubber board to prevent the rat from turning in its cage todislodge the cannulas. The femoral arterial cannula was connected to aStatham pressure transducer which in turn was attached to a polygraphfor recording arterial pressure and pulse rate. The pulse rate wasconsidered to be the heart rate.

After the blood pressure has stabilized (usually 2 hours after cessationof the anesthesia), standard agonists were injected by the i.v. route.The doses administered were: isoproterenol 0.5 μg/kg, adrenaline 2.0μg/kg, tyramine 200 μg/kg and angiotensin-I 0.25 μg/kg. The agonistswere given in random order except that tyramine was never preceded byisoproterenol as the response to tyramine seemed to be blunted after aprior injection of isoproterenol. Enough time was allowed for the bloodpressure to return to preinjection levels before the test compound wasadministered by gastric lavage. The time of drug administration wasdesignated as time zero. Heart rate and blood pressure were recorded at5, 10, 15, 30, 45 and 60 minutes and hourly thereafter for a period of 4hours after drug administration. At 1 and 2 hours post-drug the agonistswere again injected at the same concentration and in the same order asduring the control period.

For each compound the maximum mean fall in blood pressure was comparedto pretreatment control values and expressed as a percentage fall inblood pressure.

The compound2-[2,2-dimethyl-6-(trifluoromethoxy)-2H-1-benzopyran-4-yl]-2,3-dihydro-1H-isoindol-1-oneof the present invention lowers the blood pressure in spontaneouslyhypertensive rats by 44% at 30 minutes after dosing when administered ata dose of 10 milligrams per kilogram.

The compound2-[2,2-dimethyl-6-(trifluoromethoxy)-2H-1-benzopyran-4-yl]-1,2-dihydro-3H-pyrrolo[3,4-c]pyridin-3-oneof the present invention lowers blood pressure in spontaneouslyhypertensive rats by 51% at 30 minutes after dosing when administered ata dose of 5 milligrams per kilogram.

Compounds of formula (I) may be administered alone or with a diuretic,such as hydrochlorothiazide, or a b-blocker, such as propranolol orcetamolol in a suitable unit dose form.

We claim:
 1. The compound designated2-[2,2-dimethyl-6-(trifluoromethoxy)-2H-1-benzopyran-4-yl]-1,2-dihydro-3H-pyrrolo[3,4-c]pyridin-3-oneor the pharmaceutically acceptable salts thereof.